Direct compression polymer tablet core

ABSTRACT

The present invention provides a tablet core which comprises at least about 95% by weight of an aliphatic amine polymer. The invention also provides a method of producing a tablet core comprising at least about 95% by weight of an aliphatic amine polymer resin The method comprises the step of compressing the aliphatic amine polymer to form the tablet core. The tablet core can further include one or more excipients. In this embodiment, the method of producing the tablet core comprises the steps of: (1) hydrating the aliphatic amine polymer to the desired moisture level; (2) blending the aliphatic amine polymer with the excipients in amounts such that the polymer comprises at least about 95% by weight of the resulting blend; and (3) compressing the blend to form the tablet core. The present invention further relates to a coated tablet comprising an aliphatic amine polymer core wherein the coating is a water based coating.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/691,429, filed Oct. 18, 2000, which claims the benefit of U.S.Provisional Application No. 60/160,258, filed Oct. 19, 1999, and U.S.Provisional Application No. 60/174,227, filed Jan. 3, 2000. The entireteachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] A number of polymeric materials having useful therapeuticactivity have been described for treatment of various conditions such ashyperlipidemia and hyperphosphatemia. Many of these polymeric materialsfunction as non-absorbed ion exchange resins in the digestive tract.Such non-absorbed polymeric materials bind or otherwise sequester atarget molecule and facilitate its removal from the body via thegastrointestinal tract. Examples of such resins include: Colestipol andCholestyramine useful as orally administered cholesterol loweringagents; a variety of aliphatic amine polymers disclosed U.S. Pat. Nos.5,496,545 and 5,667,775 useful as phosphate binders particularly forremoving phosphate from patients suffering from renal failure; and otheraliphatic amine polymers disclosed in U.S. Pat. No. 5,624,963, U.S. Pat.No. 5,679,717, WO98/29107 and WO99/22721 useful as cholesterol loweringagents.

[0003] Non-absorbed polymer therapeutics have traditionally presented anumber of formulation challenges as the dosages are generally very large(gram quantities), and the resins tend to be extremely hydrophilic. Themost desirable formulation for oral delivery of a therapeutic is adirect compression tablet formulation. However, not all therapeutics,particularly given the high dose requirements of polymeric ion exchangetherapeutics, lend themselves to a tablet formulation. Even if suchmaterials could be rendered into a tablet, it is generally not possiblewithout the significant addition of other materials which assist in thetableting process. Ultimately the addition of any materials other thanthe active ingredient is undesirable given the dose requirement of theactive ingredient. Ideally the tablet should contain as much activeingredient as possible with little else in the way of additionalmaterials such that the tablet is as small as possible and easy toadminister to the patient.

[0004] In addition, once the polymeric materials are compressed into atablet, the tablet requires a coating for ease of administration to thepatient. It has been discovered that the core polymeric material tendsto be very hygroscopic, and thus will swell immediately upon contactwith the inside of the mouth. Most coatings contain water, and thus itwas believed that coating such tablets with a water-based coating wouldbe impossible because the hygroscopic tablets would swell during thecoating process. Thus providing a tablet core comprising a hygroscopicmaterial such that a suitable coating may be used in conjunction withthat core, is another significant challenge to providing the polymericactive ingredient in tablet form.

[0005] There is a need to provide suitable dosage forms for polymericion exchange materials, particularly for hydrophilic aliphatic aminepolymers useful as therapeutic agents, which minimize the overall amountof material administered to the patient, which are easy to administerorally, and which are stable upon production and storage.

SUMMARY OF THE INVENTION

[0006] The present invention provides a tablet core which comprises atleast about 95% by weight of an aliphatic amine polymer. In a preferredembodiment, the aliphatic amine polymer resin is a cross-linkedpolyallylamine resin. The aliphatic amine polymer is preferablyhydrated. The hydrated polymer can, for example, comprise from about 5%water by weight or greater.

[0007] The invention also provides a method of producing a tablet corecomprising at least about 95% by weight of an aliphatic amine polymerresin. The method comprises the step of compressing the aliphatic aminepolymer to form the tablet core. The tablet core can further include oneor more excipients. In this embodiment, the method of producing thetablet core comprises the steps of: (1) hydrating or drying thealiphatic amine polymer to the desired moisture level; (2) blending thealiphatic amine polymer with the excipients in amounts such that thepolymer comprises at least about 95% by weight of the resulting blend;and (3) compressing the blend to form the tablet core. The presentinvention further relates to a coated tablet wherein the coatingcomprises a water based coating.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The FIGURE is a table comprising data showing formulations andresponses for sevelamer hydrochloride compressed tablet cores.

DETAILED DESCRIPTION OF THE INVENTION

[0009] A number of polymeric materials having useful therapeuticactivity have been discussed above. In particular, aliphatic aminepolymers have been disclosed which are useful in methods of lowering theserum phosphate level of a patient and lowering the serum cholesterollevel of a patient. For example an epichorohydrin-cross-linkedpoly(allylamine hydrochloride) resin (U.S. Pat. Nos. 5,496,545 and5,667,775), also referred to as sevelamer hydrochloride or sevelamer andmarketed as RENAGEL®, has been shown to be effective at removingphosphate from human patients suffering from renal failure.Therapeutically effective dosages of sevelamer hydrochloride are large,typically on the order of 4 to 6 grams per day. Consequently,development of a dosage form of this and similar resins which minimizesthe amount of excipient material is desirable.

[0010] The present invention provides a tablet core comprising at leastabout 95% by weight of an aliphatic amine polymer. The aliphatic aminepolymer resin can be any of the aliphatic amine resins described in U.S.Pat. Nos. 5,496,545; 5,667,775; 5,624,963; 5,703,188; 5,679,717;5,693,675, 5,607,669; 5,618,530; 5,487,888; and 5,702,696, each of whichis hereby incorporated herein by reference in its entirety. Othersuitable aliphatic amine polymers are disclosed in U.S. Ser. Nos.08/670,764; 08/959,471, and 08/979,096, each of which is herebyincorporated by reference herein in its entirety. In a particularlypreferred embodiment, the aliphatic amine polymer is polyallylamine,polyvinylamine, poly(diallylamine) or poly(ethyleneimine) or a saltthereof with a pharmaceutically acceptable acid. The aliphatic aminepolymer is optionally substituted at one or more nitrogen atoms with analkyl group or a substituted alkyl group such as a trialkylammonioalkylgroup. The aliphatic amine polymer can optionally be cross-linked, forexample via a multifunctional monomer or a bridging group which connectstwo amino nitrogen atoms from two different polymer strands. In apreferred embodiment, the aliphatic amine polymer resin is hydrated. Forsevelamer hydrochloride, in particular, the compressibility is stronglydependent upon the degree of hydration (moisture content) of the resin.Preferably, the resin has a moisture content of about 5% by weight orgreater, more preferably, the moisture content is from about 5% to about9% by weight, and most preferably about 7% by weight. It is to beunderstood that in embodiments in which the polymer resin is hydrated,the water of hydration is considered to be a component of the resin.Thus, in this embodiment, the tablet core comprises at least about 95%,preferably at least about 96%, and more preferably at least about 98% byweight of the hydrated polymer, including the water of hydration.

[0011] The tablet can further comprise one or more excipients, such ashardeners, glidants and lubricants, which are well known in the art.Suitable excipients include colloidal silicon dioxide, stearic acid,magnesium silicate, calcium silicate, sucrose, calcium stearate,glyceryl behenate, magnesium stearate, talc, zinc stearate and sodiumstearylflumarate. The excipients can represent from 0 to about 5% of thetablet core by weight.

[0012] The tablet core of the invention is prepared by a methodcomprising the steps of: (1) hydrating or drying the aliphatic aminepolymer to the desired moisture level; (2) blending the aliphatic aminepolymer with any excipients to be included in amounts such that thepolymer comprises at least about 95% by weight of the resulting blend;and (3) compressing the blend using conventional tableting technology.

[0013] The invention also relates to a stable, swallowable coatedtablet, particularly a tablet comprising a hydrophilic core, such as atablet comprising an aliphatic amine polymer, as described above. In oneembodiment, the coating composition comprises a cellulose derivative anda plasticizing agent. The cellulose derivative is, preferably,hydroxypropylmethylcellulose (HPMC). The cellulose derivative can bepresent as an aqueous solution. Suitable hydroxypropylmethylcellulosesolutions include those containing HPMC low viscosity and/or HPMC highviscosity. Additional suitable cellulose derivatives include celluloseethers useful in film coating formulations. The plasticizing agent canbe, for example, an acetylated monoglyceride such as diacetylatedmonoglyceride, The coating composition can further include a pigmentselected to provide a tablet coating of the desired color. For example,to produce a white coating, a white pigment can be selected, such astitanium dioxide.

[0014] In one embodiment, the coated tablet of the invention can beprepared by a method comprising the step of contacting a tablet core ofthe invention, as described above, with a coating solution comprising asolvent, at least one coating agent dissolved or suspended in thesolvent and, optionally, one or more plasticizing agents. Preferably,the solvent is an aqueous solvent, such as water or an aqueous buffer,or a mixed aqueous/organic solvent. Preferred coating agents includecellulose derivatives, such as hydroxypropylmethylcellulose. Typically,the tablet core is contacted with the coating solution until the weightof the tablet core has increased by an amount ranging from about 4% toabout 6%, indicating the deposition of a suitable coating on the tabletcore to form a coated tablet.

[0015] In one preferred embodiment, the solids composition of thecoating solution is: Material % W/W HPMC low viscosity Type 2910, cUSP38.5% HPMCE high viscosity Type 2910, cUSP 38.5% diacetylatedmonoglyceride 23.0%

[0016] Tablets may be coated in a rotary pan coater as is known in theart or any other conventional coating apparatus such as a column coateror a continuous coater.

[0017] Astonishingly, it has been found that an aqueous coatingdispersion is suitable as a coating solution for tablets comprising ahygroscopic, or water-swellable substance, such as an aliphatic aminepolymer tablet. For example, the coating composition provides a strong,elastic and moisture-permeable coating without causing significantconcomitant swelling of the tablet core during the coating process. In apreferred embodiment, the coating composition provides a tablet coatingwhich withstands the swelling and contraction of sevelamer hydrochloridetablets during exposure to varying humidity levels and other knownstability tests. Further, the coating composition can be used to coatother aliphatic amine polymer tablets without excessive uptake by thetablet core of water from the coating solution during the coatingprocess.

[0018] The present invention also relates to the use of an aliphaticamine polymer as a disintegrant in a tablet. In general, in thisembodiment the aliphatic amine polymer is not the active ingredient inthe tablet, but is added to the tablet to enhance the rate ofdisintegration of the tablet following administration. This allows amore rapid release of the active agent or agents. The tablet willgenerally include the aliphatic amine polymer, one or more activeingredients, such as therapeutic agents (medicaments), and, optionally,one or more additional excipients.

[0019] The aliphatic amine polymer can be one of the aliphatic aminepolymers disclosed above, such as polyethyleneimine, polyvinylamine,polyallylamine, polydiallylamine or any of the aliphatic amine polymersdisclosed in U.S. Pat. Nos. 5,496,545 and 5,667,775 and U.S. Ser. Nos.08/777,408 and 08/964,498, the teachings of each of which areincorporated herein by reference. In one embodiment, the aliphatic aminepolymer is a cross-linked polyallylamine or a salt thereof with apharmaceutically acceptable acid. Preferably, the aliphatic aminepolymer is an epichlorohydrin-cross-linked polyallylamine or saltthereof with a pharmaceutically acceptable acid, such as sevelamer orsevelamer hydrochloride.

[0020] The tablet which includes an aliphatic amine as a disintegrantwill, generally, include a sufficient amount of the aliphatic aminepolymer to effectively enhance the rate of tablet disintegration underconditions of use. For example, if the tablet is an oral doseage formand it is desired that the tablet disintegrate in the stomach of thepatient, the tablet should include a sufficient amount of the polymer toenhance the disintegration rate of the tablet under the conditionsencountered in the stomach. The appropriate amount of the polymer to beincluded in the tablet can be determined by one skilled in the art usingknown methods. Typically, the polymer, the active ingredient oringredients and any additional fillers or excipients are combined bymixing, and the resulting mixture is compressed to form a tablet usingconventional methods. The tablet core formed in this way can then becoated, for example, as described above, or by other methods and othercoating compositions which are known in the art and suitable for theintended use of the tablet.

[0021] In one embodiment, the tablet which includes an aliphatic aminepolymer as a disintegrant is intended for administration in vivo, forexample, to a patient, such as a human. Preferably, the tablet isintended to be administered orally. In this embodiment, the activeingredient or ingredients will be a therapeutic or diagnostic agent. Thetablet can also be intended for use in vitro, for example, to deliver anactive ingredient to an aqueous environment, such as a swimming pool.

[0022] The invention will now be described in detail by reference to thefollowing examples.

EXAMPLES Example 1 Preparation and Characterization of 400 mg and 800 mgSevelamer Hydrochloride Direct Compression Tablet Cores

[0023] Preparation of Tablet Cores

[0024] 400 mg sevelamer hydrochloride tablet cores were prepared from ablend consisting of 5000.0 g sevelamer hydrochloride, 50.0 g colloidalsilicon dioxide, NF (Aerosil 200) and 50.0 g stearic acid. The sevelamerhydrochloride was hydrated to moisture content of 6% by weight. Theblend was prepared by passing the sevelamer hydrochloride and colloidalsilicon dioxide through a #20 mesh screen, transferring the mixture to a16 quart PK blender and blending for five minutes. The stearic acid wasthen passed through an oscillator equipped with a #30 mesh screen,transferred into the 16 quart PK blender and blended for five minuteswith the sevelamer hydrochloride/colloidal silicon dioxide mixture. Theresulting blend was discharged into a drum and weighed. The final blendwas then compressed on a 16 station Manesty B3B at 4 tons pressure using0.280″×0.620″ punches to give tablet cores with an average weight of 434mg. The resulting tablets consisted of 425 mg 6% hydrated sevelamerhydrochloride (equivalent to 400 mg anhydrous sevelamer hydrochloride),4.25 mg colloidal silicon dioxide and 4.25 mg stearic acid.

[0025] 800 mg sevelamer hydrochloride tablet cores were prepared from19.0 kg sevelamer hydrochloride, 0.19 kg colloidal silicon dioxide, and0.19 kg stearic acid,. The sevelamer hydrochloride had a moisturecontent of 6% by weight. The blend was prepared by passing the sevelamerhydrochloride and colloidal silicon dioxide through a #20 mesh screen,transferring the mixture to a PK blender and blending for five minutes.The stearic acid was then passed through an oscillator equipped with a#30 mesh screen, transferred into the PK blender and blended for fiveminutes with the sevelamer hydrochloride/colloidal silicon dioxidemixture. The resulting blend was then discharged into a drum andweighed. The final blend was then compressed in on a 16 station ManestyB3B at 4 tons pressure using 0.3125″×0.750″ punches to give tablets withan average weight of 866 mg. The resulting tablets consisted of 850 mg6% hydrated sevelamer hydrochloride (equivalent to 800 mg anhydroussevelamer hydrochloride), 8.0 mg colloidal silicon dioxide and 8.0 mgstearic acid.

[0026] Characterization of Tablet Cores

[0027] The tablets prepared as described above were white to off-white,oval shaped, compressed tablets. The variation of the tablets preparedfrom each blend with respect to weight, thickness, friability, hardness,disintegration time and density was assessed. Standard methods in theart were employed for each of the measurements. The results, (notshown), indicate that the hardness, friability, thickness, anddisintegration behavior of the sevelamer hydrochloride tablets all metindustry-standard criteria.

Example 2 Coating of Sevelamer Hydrochloride Tablet Cores

[0028] Compressed core tablets prepared as described in Example 1 werecoated in a coating pan with an aqueous coating solution having a solidscomposition comprising: Material % W/W HPMC low viscosity Type 2910,cUSP 38.5% HPMCE high viscosity Type 2910, cUSP 38.5% diacetylatedmonoglyceride 23.0%

[0029] The coating solution was applied to the compressed cores until aweight gain of approximately 4 to 6% was achieved. Stabilitystudies—controlled room temperature, accelerated conditions, freeze/thawand photosensitivity—for the coated sevelamer hydrochloride tablets wereconducted in accordance with those procedures known in the art anddescribed in the following references: International Committee onHarmonization (ICH) guidance “Q1A-Stability Testing of New DrugSubstances and Products” (June 1997); ICH “Q1B-Guidelines for thePhotostability Testing of New Drug Substances and Products” (November1996); and ICH guidance “Q1C-Stability Testing for New Dosage Forms”(November 1996. The results (not shown) indicate that the coated tabletsall met industry standard criteria.

Example 3 Factors Affecting the Processing and PerformanceCharacteristics of Compressed Tablets (Prior to Coating)

[0030] In order to maintain consistently acceptable compressed tablet ona per batch basis, a number of correlative tests were performed in orderto determine which factors most strongly impact the quality andintegrity of the tablets. Studies such as weight variation, tablethardness, friability, thickness, disintegration time, among others areknown to those skilled in the art and are described in the United StatesPharmacopeia (U.S.P.). “Hardness” means the measure of the force(measured herein in Newtons) needed to fracture a tablet when suchtablet is placed lengthwise on a Hardness Tester. “Friability” is themeasure of the mechanical strength of the tablet needed to withstand therolling action of a coating pan and packaging. It is measured using afriabiliator. “Thickness” is the measure of the height of the tabletusing a micrometer. “Disintegration Time” is the time necessary for thetablet to break apart in an appropriate solution at 37° C. and ismeasured in minutes.

[0031] Attainment of appropriate hardness (150-170 N hardness range) andfriability (no more than 0.8%) is important to the success of theformulation. Having tablets with high hardness and low friability isparticularly important when the tablets are to be coated as is the casewith sevelamer hydrochloride tablets.

[0032] The FIGURE provides a table listing several different sevelamerhydrochoride tablet core formulations that vary by a number of factorsincluding (actual) moisture content, and compression force used,excipient content among other variations. The data in

[0033] The FIGURE indicates that the most important factor affecting theprocessing and performance characteristics of compressed tablets is themoisture content. All formulations provided good flow with little weightvariation throughout the entire range of compositions. In addition,disintegration times were less than 5 minutes across the range ofcompositions. Thus, it appears that moisture content and compressionforce provide the most appropriate factors on which to establishoperating ranges for hardness and friability.

[0034] Equivalents

[0035] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention as defined by the appended claims.

What is claimed is:
 1. A compressed tablet comprising an effectivedisintegrating amount of polyallylamine or a salt thereof with apharmaceutically acceptable acid.
 2. The compressed tablet of claim 1,wherein the polyallylamine or salt thereof is cross-linked.
 3. Thetablet of claim 2, wherein the polyallylamine or salt thereof iscross-linked with epichlorohydrin.
 4. The tablet of claim 1, wherein thepolyallylamine or the salt thereof is not an active ingredient.